Leukocytes from patients with infectious mononucleosis (IM) show an enhanced cytotoxicity for lymphoid cell lines (LCL) which contain the Epstein-Barr virus (EBV) genome. The enhanced cytotoxicity declines during convalescence and correlates with the percentage of atypical lymphocytes in the leukocyte population. IM is a self-limiting lymphoproliferative disease usually caused by EBV, and at least part of the enhanced cytotoxicity may be specific for EBV associated antigens. However, patients with the rarer cytomegalovirus mononucleosis also have an atypical lymphocytosis and an increased capacity to kill LCL; some of the increased cytotoxicity may then have a broader specificity. Mitogens and antigens induce cytotoxic blast cells in cultures of immune lymphocytes in vitro and EBV antigens are no exception in this respect. Such cells may be the in vitro counterparts of the atypical lymphocytes of IM which are associated with destruction of cultured cells. We propose to characterize and compare the atypical lymphocytes induced in vivo during mononucleosis and the blast cells induced in vitro by virus antigens. Subpopulations of lymphocytes will be isolated by techniques which take advantage of variation in types and density of surface receptors. Isolated subpopulations will be examined in standard 51Cr release assays for their capacity to kill a variety of target cells. These will include both cultured cells and fresh human tumor tissues. The cytotoxic lymphocytes in the blood of patients with EBV IM are probably part of the mechanism by which the normal immunocompetent host copes with transformed proliferating cells. Information about the nature and generation of such cytotoxic cells may thus be relevant both to understanding and immunotherapy of proliferation in malignant diseases.